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Gradient system characterization of a 1.5 T MR-Linac with application to 4D UTE imaging for adaptive MR-guided radiotherapy of lung cancer.
No full textPURPOSE: To measure the gradient system transfer function (GSTF) of an MR-Linac (Elekta Unity, Stockholm, Sweden) using an accessible phantom-based method and to apply trajectory corrections for UTE image reconstruction in the context of MR-guided radiotherapy of lung cancer. METHODS: The first-order GSTF of a 1.5 T, split gradient Elekta Unity MR-Linac was measured using a thin-slice technique to characterize gradient system imperfections for each physical gradient axis (X, Y, Z). Repeatability measurements of the GSTF were performed 48 h apart. The GSTF was applied to trajectory correction in multi-echo UTE image reconstruction (TEs = 0.176, 1.85, 3.52 ms) to allow for UTE-Dixon inputs in the generation of synthetic CT. Images were acquired in an anthropomorphic phantom and in two free-breathing lung cancer patients. For patient scans, respiratory-correlated 4D-MR images were reconstructed using self-navigation and an iterative compressed-sensing algorithm. RESULTS: The GSTF magnitude was similar across the X/Y/Z axes up to ˜6 kHz. The GSTF phase was similar between the X/Y/Z components up to ˜3 kHz. Repeatability measurements demonstrated minimal variations corresponding to a system delay difference of 0.06 μs. Corrected UTE trajectory spokes are shifted approximately 1 m-1 compared to the nominal k-space location. Corrected phantom and patient UTE images exhibited improved signal uniformity and contrast and reduced halo and signal loss artifacts. Trajectory correction for the later TE images did not improve overall image quality. CONCLUSION: The proposed GSTF measurement method using standard MR-Linac hardware enables successful trajectory correction in UTE imaging reconstruction, with applications to lung synthetic CT generation for MR-guided radiotherapy
Studies in people with increased genetic risk of prostate cancer
No full textProstate cancer (PrCa) causes a significant healthcare burden worldwide and is currently without a globally-agreed screening programme, which is urgently needed to aid earlier diagnosis and intervention when the disease is still at a curable stage.
There is a paucity of data on targeted screening in those at higher genetic risk of developing PrCa, particuarly, in persons of Black African/African-Caribbean ancestry. This PhD aimed to investigate targeted PrCa screening in persons at higher genetic risk of PrCa and correlate prostate specific antigen (PSA), magnetic resonance imaging (MRI) and prostate biopsy results with genetic biomarkers.
My PhD has investigated targeted screening in those at higher risk of developing PrCa using a polygenic risk score (PRS) and in persons at higher risk due to their genetic ancestry, reporting on two studies: the BARCODE1 and PROFILE PAC studies.
The BARCODE1 study was carried out in persons of European ancestry and used a PrCa 130SNP PRS. Those with a PRS ≥90th centile were invited for PrCa screening using MRI and transperineal biopsy, irrespective of PSA result. Of 6,393 participants that had their PRS calculated 745 (11.7%) had a PRS ≥90th centile, 468 underwent MRI and biopsy and 187 had PrCa detected. 103 of these PrCas required clinical management. Had these persons been managed through the current UK PrCa diagnostic pathway, 73 would not have received a diagnosis. It has helped to inform the upcoming UK-based TRANSFORM study and has been accepted for publication in the New England Journal of Medicine.
The PROFILE study PAC cohort assessed persons of African/African Caribbean ancestry. In 73 who have undergone baseline biopsy, 26 PrCas were detected (35.6%). Again, in this high-risk cohort, had the current UK diagnostic pathway been used, 25% (3/12) with clinically significant PrCa would not have been referred for biopsy based on PSA and MRI findings. A total of 300 have been recruited to this study and I report on the PRS and rare variant analysis in 243 of the participants.
This work has added to the landscape of PrCa screening and early diagnosis of those at higher genetic risk of PrCa
Clinical and Molecular Profiling of Colorectal Cancer: A Comprehensive Cohort Study of BRAF-Mutated Cases from a Tertiary Centre.
No full textIntroduction: Increasingly, identification of BRAF mutation in colorectal cancer is used to guide management and predict cancer behaviour. There is, however, still significant diversity within this cohort of patients, both in terms of clinical phenotype and treatment outcomes. This may be explained, at least in part, by differences between classes of BRAF mutations and the presence of concomitant mutations. Methods: We present a retrospective cohort study of sequential patients diagnosed with BRAF-mutated (V600 and non-V600) colorectal cancer between 2014 and 2022. Information regarding presentation, treatment outcomes and molecular subtype was identified using the electronic medical record. Results: This study included 406 patients with BRAF-mutated colorectal cancer, 253 (228 V600BRAF) of whom had localised disease and 153 (137 V600BRAF) with metastatic disease at the time of diagnosis. In patients with localised disease at diagnosis, the V600BRAF mutation was associated with older median age (73 vs. 63 years, p = 0.04) and a higher prevalence of right-sided primary (73% vs. 40%, p < 0.01), mismatch repair deficiency (56% vs. 8%, p < 0.01), and faster time to disease relapse (p = 0.006). In the metastatic setting, non-V600BRAF mutation was associated with a higher prevalence of KRAS mutation (27% vs. 1%, p < 0.01), NRAS mutation (14% vs. 3%, p = 0.04) and PIK3CA mutation (33% vs. 8%, p = 0.02). Mismatch repair deficiency was more common in patients with V600BRAF mutations than in those with non-V600BRAF mutations (20% vs. 0%, p = 0.01). The median survival of patients with the V600BRAF mutation was 14 months, and 34 months in those with non-V600BRAF mutations. Concomitant RNF43 mutation in metastatic disease, was associated with a significantly higher incidence of disease control from combined BRAF and EGFR inhibition, when compared to those without an RNF43 mutation (100% vs. 54%, p = 0.02). Conclusions: Presentation and outcomes of BRAF-mutated colorectal cancer are heterogenous. The type of BRAF mutation, and the presence of concomitant RNF43 mutation, may explain some of the differences in cancer behaviour. Routine reporting of RNF43 mutations would assist clinicians to give more personalised treatment recommendations
The landscape of microbial associations in human cancer.
No full textOncomicrobes are estimated to cause 15% of cancers worldwide. When cancer whole-genome sequencing (WGS) data are collected, the microbes present are also sequenced, allowing the investigation of potential etiological and clinical associations. Interrogating the microbial community for 8908 patients encompassing 22 cancer types from the Genomics England WGS dataset revealed that only colorectal tumors exhibited unmistakably distinct microbial communities that can reliably be used to distinguish anatomical site [positive predictive value (PPV) = 0.95]. This pattern was validated in two independent datasets. Potential clinical relevance uncovered by our analyses included accurate detection of alphapapillomaviruses [human papillomavirus (HPV)] in oral cancers, when compared with current clinical standards, and the detection of rare, highly pathogenic viruses such as human T-lymphotropic virus-1. Biomarker investigations demonstrated statistically significant associations (P < 0.05) between a subset of anaerobic bacteria and survival in certain subtypes of sarcoma. Our results contradict previous claims that each cancer type has a distinct microbiological signature but highlight the potential value of microbial analysis for certain cancers as WGS of tumor samples becomes common in the clinic
Validating data from multiplex assays of variant effect: A CanVIG-UK national survey of NHS clinical scientists.
No full textAdvances in technology have made it possible for multiplex assays of variant effect (MAVEs) to systematically generate functional data for thousands of genetic variants. Robust clinical validation and accessible online resources for MAVE data have previously been identified as barriers to the clinical adoption of new MAVEs. We delivered a survey during the November 2024 Cancer Variant Interpretation Group UK (CanVIG-UK) meeting comprising National Health Service (NHS) clinical scientists and clinical geneticists and received 46 responses from individuals regularly performing variant classification for diagnostic reporting. Only 35% reported they would accept clinical validation of the MAVE provided by the authors who conducted the assay; 20% reported they would attempt clinical validation themselves, and 61% would await clinical validation by a trusted central body. 72% reported they would use MAVE data ahead of a formal peer-reviewed publication if reviewed and clinically validated by a trusted central body. When scoring central bodies on a scale of 1-5 for confidence in their review and validation of MAVEs, CanVIG-UK (median = 5), variant curation expert panels (VCEPs; median = 5), and ClinGen SVI Functional Working Group (median = 4) all scored highly. Participants supported making variant-level data accessible via a relevant web resource (although the majority of participants expressed that additional assay-level or variant-level information would have a low likelihood of altering validation scores provided by a trusted central body). These findings, from a comparatively homogeneous clinical diagnostic group operating in a resource-constrained healthcare setting, indicate that clinical application of new MAVEs for variant classification will be delayed unless robust clinical validations are performed by a trusted central body and made readily accessible
Elucidating predictors of treatment response in oesophago-gastric cancers
No full textCytotoxic chemotherapy has underpinned the treatment landscape of advanced oesophago-gastric adenocarcinoma (OGA) for decades. However, the median overall survival following first-line platinum-fluoropyrimidine chemotherapy in human epidermal growth factor (HER2)-negative disease remains limited at less than 12 months. This highlights a need for innovative therapeutic approaches, using both novel drugs and unexploited treatment settings.
The PLATFORM study is a multi-centre, randomised, adaptive phase II study assessing the efficacy of maintenance therapies in advanced OGA patients with radiologically proven disease control or response following 18 weeks of first-line platinum-fluoropyrimidine chemotherapy. To evaluate the impact of maintenance therapies on progression-free survival (PFS), the study design allows simultaneous recruitment into multiple interventional arms which are independently compared against active surveillance. Results from the PLATFORM study showed that maintenance durvalumab did not prolong PFS compared to active surveillance (median PFS: 3.0 versus 3.2 months respectively, hazard ratio 0.84; 95% confidence interval 0.62 – 1.14; one-sided p value 0.13).
To investigate the effect of predictive biomarkers on identifying patients who may benefit from maintenance durvalumab, exploratory analyses of programmed death ligand-1 Combined Positive Score (CPS) expression were conducted. Maintenance durvalumab did not improve median PFS or overall survival (OS) in patient with CPS ≥5 when compared to those with CPS <5 tumours. Further evaluation using a novel tumour microenvironment (TME) RNA-based panel which classifies the TME along immune and angiogenic axes showed that patient treated with durvalumab with a high immune score (biomarker-positive) had higher 12-month PGS and 24- month OS rates compared to those with a low immune score (biomarker-negative), Within the CPS ≥5 population assigned to durvalumab, a numerical improvement in 12- and 24-months OS rates were also seen in biomarker-positive patients when compared to those who were biomarker-negative.
Signe
De Novo-Designed APC/C Inhibitors Provide a Rationale for Targeting RING-Type E3 Ubiquitin Ligases.
No full textThe ubiquitin system represents an attractive pharmacological target for numerous pathological processes, including cancer and neurodegeneration. RING domain-containing E3 ubiquitin ligases constitute the largest class of ubiquitin enzymes, providing a scaffold for substrate recognition and catalysis. Their shallow groove recognition interfaces involving discontinuous epitopes and a lack of defined binding pockets have largely rendered them undruggable. Inspired by natural RING inhibitors, we have developed a pharmacophore-based strategy for the rational design of peptidomimetics targeting RING domains, and we demonstrate its feasibility by using the macromolecular APC/C complex (anaphase-promoting complex/cyclosome). We designed scaffolds binding to the APC/C RING domain and efficiently inhibiting its activity in vitro. Iterative structure-based design and experimental studies to optimize their chemical stability, permeability, and specificity lead to new hydrocarbon-stapled-based molecules inhibiting APC/C in vitro and in cancer cells. Our results provide a robust rationale for targeting RING-containing enzymes of therapeutic value and promising leads for clinical APC/C inhibition
Projected Lifetime Cancer Risks From Current Computed Tomography Imaging.
No full textIMPORTANCE: Approximately 93 million computed tomography (CT) examinations are performed on 62 million patients annually in the United States, and ionizing radiation from CT is a known carcinogen. OBJECTIVE: To project the number of future lifetime cancers in the US population associated with CT imaging in 2023. DESIGN, SETTING, AND PARTICIPANTS: This risk model used a multicenter sample of CT examinations prospectively assembled between January 2018 and December 2020 from the University of California San Francisco International CT Dose Registry. Data analysis was conducted from October 2023 to October 2024. MAIN OUTCOMES AND MEASURES: Distributions of CT examinations and associated organ-specific radiation doses were estimated by patient age, sex, and CT category and scaled to the US population based on the number of examinations in 2023, quantified by the IMV national survey. Lifetime radiation-induced cancer incidence and 90% uncertainty limits (UL) were estimated by age, sex, and CT category using National Cancer Institute software based on the National Research Council's Biological Effects of Ionizing Radiation VII models and projected to the US population using scaled examination counts. RESULTS: An estimated 61 510 000 patients underwent 93 000 000 CT examinations in 2023, including 2 570 000 (4.2%) children, 58 940 000 (95.8%) adults, 32 600 000 (53.0%) female patients, and 28 910 000 (47.0%) male patients. Approximately 103 000 (90% UL, 96 400-109 500) radiation-induced cancers were projected to result from these examinations. Estimated radiation-induced cancer risks were higher in children and adolescents, yet higher CT utilization in adults accounted for most (93 000; 90% UL, 86 900-99 600 [91%]) radiation-induced cancers. The most common cancers were lung cancer (22 400 cases; 90% UL, 20 200-25 000 cases), colon cancer (8700 cases; 90% UL, 7800-9700 cases), leukemia (7900 cases; 90% UL, 6700-9500 cases), and bladder cancer (7100 cases, 90% UL, 6000-8500 cases) overall, while in female patients, breast was second most common (5700 cases; 90% UL, 5000-6500 cases). The largest number of cancers was projected to result from abdomen and pelvis CT in adults, reflecting 37 500 of 103 000 cancers (37%) and 30 million of 93 million CT examinations (32%), followed by chest CT (21 500 cancers [21%]; 20 million examinations [21%]). Estimates remained large over a variety of sensitivity analyses, which resulted in a range of 80 000 to 127 000 projected cancers across analyses. CONCLUSIONS AND RELEVANCE: This study found that at current utilization and radiation dose levels, CT examinations in 2023 were projected to result in approximately 103 000 future cancers over the course of the lifetime of exposed patients. If current practices persist, CT-associated cancer could eventually account for 5% of all new cancer diagnoses annually
Pilot of lifestyle InterventiON to reducE brEast cancer Risk (PIONEER): the development, implementation and lessons from a randomised controlled study
No full textThis thesis describes current understanding of fixed and modifiable breast cancer risk factors. It
goes on to describe the development and results of a randomised controlled pilot study to reduce
breast cancer risk through lifestyle change, as well as describing the experience of running a
preventative therapy clinic. It also discusses the lessons learnt through running a lifestyle change
pilot study to reduce breast cancer risk, and improvements which could be made to future studies
Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers.
No full textPURPOSE: Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records. METHODS: We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks. RESULTS: There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 [95% CI, 11.8 to 20.2]), ovarian (SIR, 44.0 [95% CI, 31.4 to 59.9]), combined nonbreast/ovarian (SIR, 2.18 [95% CI, 1.59 to 2.92]), colorectal (SIR, 4.80 [95% CI, 2.62 to 8.05]), and endometrial (SIR, 2.92 [95% CI, 1.07 to 6.35]) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 [95% CI, 5.45 to 10.6]), ovarian (SIR, 16.8 [95% CI, 10.3 to 26.0]), pancreatic (SIR, 5.42 [95% CI, 2.09 to 12.5]), and combined nonbreast/ovarian (SIR, 1.68 [95% CI, 1.24 to 2.23]) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 [95% CI, 2.65 to 4.90]), ovarian (HR, 33.0 [95% CI, 19.1 to 57.1]), combined nonbreast/ovarian (HR, 1.45 [95% CI, 1.05 to 2.01]), and colorectal (HR, 2.93 [95% CI, 1.53 to 5.62]) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 [95% CI, 1.70 to 3.40]), ovarian (HR, 12.0 [95% CI, 6.70 to 21.5]), and pancreatic (HR, 3.56 [95% CI, 1.34 to 9.48]) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% (BRCA1 carriers), 12%/3.0%/6.2% (BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 [95% CI, 1.19 to 146]) and prostate (HR, 5.61 [95% CI, 1.96 to 16.0]) SPC risks than noncarriers. CONCLUSION: Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures